WO2023004440A2 - Polythérapies à base d'agonistes de sting comprenant des cytokines - Google Patents

Polythérapies à base d'agonistes de sting comprenant des cytokines Download PDF

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WO2023004440A2
WO2023004440A2 PCT/US2022/074120 US2022074120W WO2023004440A2 WO 2023004440 A2 WO2023004440 A2 WO 2023004440A2 US 2022074120 W US2022074120 W US 2022074120W WO 2023004440 A2 WO2023004440 A2 WO 2023004440A2
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patient
sting agonist
cytokine
antibody
administered
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PCT/US2022/074120
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English (en)
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WO2023004440A3 (fr
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Zhijian Chen
Lijun Sun
Youtong Wu
Huiling TAN
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Immunesensor Therapeutics, Inc.
The Board Of Regents Of The University Of Texas System
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Priority to CA3226976A priority Critical patent/CA3226976A1/fr
Priority to AU2022315305A priority patent/AU2022315305A1/en
Publication of WO2023004440A2 publication Critical patent/WO2023004440A2/fr
Publication of WO2023004440A3 publication Critical patent/WO2023004440A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/208—IL-12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2046—IL-7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2066—IL-10
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2086—IL-13 to IL-16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • This disclosure also pertains to the use of a STING agonist (such as a cyclic dinucleotide), a cytokine (such as an interleukin), and an immune checkpoint inhibitor to treat certain diseases or disorders, including cancer. 3. BACKGROUND [0003] The treatment of advanced solid tumor malignancies as well as many hematologic malignancies continues to be defined by high unmet medical need. In most settings, treatment with cytotoxic chemotherapy and targeted kinase inhibitors leads to the emergence of drug-resistant tumor clones and subsequent tumor progression and metastasis. [0004] In recent years, notable success has been achieved through alternate approaches oriented around activation of immune-mediated tumor destruction. The immune system plays a pivotal role in defending humans and animals against cancer.
  • the anti-tumor effect is controlled by positive factors that activate anti-tumor immunity and negative factors that inhibit the immune system.
  • Negative factors that inhibit anti-tumor immunity include immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA- 4), programmed cell death 1 (PD-1), and programmed death-ligand 1 (PD-L1).
  • Immuno- oncology (IO) approaches including antibodies against these checkpoint proteins, have shown remarkable efficacy in several types of human cancers. [0005]
  • existing cancer immunotherapy through immune checkpoint blockade is effective for only a small fraction (on average 20-30%) of cancer patients.
  • TILs tumor-infiltrating leukocytes
  • CD8 cluster of differentiation 8
  • TILs tumor-infiltrating leukocytes
  • a major thrust of ongoing cancer drug development research remains focused on transforming “cold” tumor cells into “hot” tumor cells in order to achieve better tumor control across a wider array of patients.
  • the innate immune system which is the first line of defense against pathogens and cancer cells, is important for turning the non-inflamed tumors (“cold”) into an inflamed (“hot”) microenvironment.
  • cGAS- STING pathway involving the protein Cyclic GMP-AMP Synthase (cGAS)
  • cGAS Cyclic GMP-AMP Synthase
  • cGAS is a DNA sensing enzyme that activates the type-I interferon pathway.
  • cGAS Upon binding to DNA, cGAS is activated to synthesize the cyclic dinucleotide (CDN) 2’3’-cyclic-GMP-AMP (2’3’-cGAMP), which then functions as a secondary messenger that binds to and activates the adaptor protein STING.
  • CDN cyclic dinucleotide
  • 2’3’-cGAMP cyclic-GMP-AMP
  • STING then activates a signal transduction cascade leading to the production of type-I interferons, cytokines, and other immune mediators.
  • cytokine production is essential for generating anti-tumor immunity
  • high cytokine levels pose a safety concern. Specifically, high cytokine levels can evoke a dangerous inflammatory response in cancer patients undergoing immunotherapy, thereby discouraging the use of cytokines in IO applications.
  • Selection of the type and amount of an appropriate cytokine to leverage its anti-tumor effect while reducing or limiting its systemic toxicity has remained a challenging unmet need.
  • therapies that can provoke specific and systemic immune responses to tumors throughout the body, including those tumors that are not or cannot be treated directly (i.e., through an abscopal effect), such as due to their location or size. 4.
  • the disclosure provides methods of administering STING agonists to patients, such as human cancer patients, in combination with cytokines, and optionally in further combination with one or more immune checkpoint inhibitors, such as inhibitors of CTLA-4, PD-1, and/or PD-L1, particularly antibody inhibitors of these proteins.
  • the present disclosure also provides combination therapies capable of use in such methods and treatments.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • both the STING agonist and the cytokine are administered intratumorally to the patient.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient and wherein the patient exhibits reduced recurrence of the tumors following treatment, including in the absence of further treatment.
  • both the STING agonist and the cytokine are administered intratumorally to the patient
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically administering an effective amount of an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) to the cancer patient.
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist (such as a CDN), a cytokine (such as an interleukin), and an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti- CTLA-4 antibody) to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the immune checkpoint inhibitor is administered systemically to the cancer patient.
  • a STING agonist such as a CDN
  • a cytokine such as an interleukin
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti- CTLA-4 antibody
  • the disclosure provides a method of augmenting the anti-tumor response of a cancer patient, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • the STING agonist or the cytokine is intratumorally administered to the patient.
  • both the STING agonist and the cytokine are administered intratumorally to the patient.
  • the disclosure provides a method of augmenting the anti- tumor response of a cancer patient, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically administering an effective amount of an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) to the cancer patient.
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the disclosure provides a method of augmenting the anti-tumor response of a cancer patient, comprising conjointly administering effective amounts of a STING agonist (such as a CDN), a cytokine (such as an interleukin), and an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the immune checkpoint inhibitor is administered systemically to the cancer patient.
  • a STING agonist such as a CDN
  • a cytokine such as an interleukin
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • a STING agonist and a cytokine is intratumorally administered to the patient.
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically administering an effective amount of an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) to the cancer patient.
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient, comprising conjointly administering effective amounts of a STING agonist (such as a CDN), a cytokine (such as an interleukin), and an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD- L1 antibody, or an anti-CTLA-4 antibody) to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the immune checkpoint inhibitor is administered systemically to the cancer patient.
  • a STING agonist such as a CDN
  • a cytokine such as an interleukin
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD- L1 antibody, or an anti-CTLA-4 antibody
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising, conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • the STING agonist or the cytokine is intratumorally administered to the patient.
  • both the STING agonist and the cytokine are administered intratumorally to the patient.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically administering an effective amount of an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti- CTLA-4 antibody) to the cancer patient.
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti- CTLA-4 antibody
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist (such as a CDN), a cytokine (such as an interleukin), and an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the immune checkpoint inhibitor is administered systemically to the cancer patient.
  • a STING agonist such as a CDN
  • a cytokine such as an interleukin
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the disclosure provides a method of treating of tumors in a cancer patient in need thereof, comprising causing a STING agonist (such as a CDN), a cytokine (such as an interleukin), and an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) to be concurrently present in the patient’s body.
  • a STING agonist such as a CDN
  • a cytokine such as an interleukin
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the method comprises administering an effective amount of the cytokine to the patient, wherein the patient has already been administered the STING agonist and the immune checkpoint inhibitor. In yet another particular embodiment, the method comprises administering an effective amount of the immune checkpoint inhibitor to the patient, wherein the patient has already been administered the STING agonist and the cytokine.
  • the disclosure provides a method of reducing recurrence of tumors in a patient, comprising causing a STING agonist (such as a CDN), a cytokine (such as an interleukin), and an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD- L1 antibody, or an anti-CTLA-4 antibody) to be concurrently present in the patient’s body.
  • a STING agonist such as a CDN
  • a cytokine such as an interleukin
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD- L1 antibody, or an anti-CTLA-4 antibody
  • the method comprises administering an effective amount of the cytokine to the patient, wherein the patient has already been administered the STING agonist and the immune checkpoint inhibitor. In yet another particular embodiment, the method comprises administering an effective amount of the immune checkpoint inhibitor to the patient, wherein the patient has already been administered the STING agonist and the cytokine.
  • the disclosure provides a method of preventing recurrence of tumors in a patient, comprising causing a STING agonist (such as a CDN), a cytokine (such as an interleukin), and an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) to be concurrently present in the patient’s body.
  • a STING agonist such as a CDN
  • a cytokine such as an interleukin
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the method comprises administering an effective amount of the cytokine to the patient, wherein the patient has already been administered the STING agonist and the immune checkpoint inhibitor. In yet another particular embodiment, the method comprises administering an effective amount of the immune checkpoint inhibitor to the patient, wherein the patient has already been administered the STING agonist and the cytokine.
  • the disclosure provides a combination therapy, such as for treating tumors in a cancer patient in need thereof, comprising a STING agonist and a cytokine, wherein the STING agonist or the cytokine is formulated for intratumoral administration to the patient. In certain embodiments, both the STING agonist and the cytokine are formulated for intratumoral administration to the patient.
  • the disclosure provides a combination therapy, such as for treating tumors in a cancer patient in need thereof, wherein both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the combination therapy further comprises an immune checkpoint inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody) formulated for systemic administration to the cancer patient.
  • an immune checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the disclosure provides a mixture comprising a STING agonist, a cytokine, and an immune checkpoint inhibitor. In some embodiments the mixture further comprises human plasma.
  • the disclosure provides a mixture comprising a STING agonist that is a CDN; a cytokine that is an interleukin; an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody; and human plasma.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient and wherein the patient exhibits reduced recurrence of the tumors following treatment.
  • both the STING agonist and the cytokine are administered intratumorally to the patient.
  • the STING agonist employed in the methods, uses, and combination therapies disclosed herein is a CDN, such as a compound (“Compound A”) having the following structure, or a pharmaceutically acceptable salt thereof:
  • Compound A is a cyclic dinucleotide that is capable of activating STING and was described in U.S. Published Application No.2018/0230177, which is incorporated herein by reference.
  • Various salt forms of Compound A can be administered to a cancer patient. For instance, in one embodiment, an effective amount of a sodium salt of Compound A is administered to the cancer patient.
  • any reference to Compound A in the disclosure also includes pharmaceutically acceptable salts thereof.
  • Compound A is used in the methods, uses, and combination therapies disclosed here in combination with the cytokine IL-12.
  • the cytokine employed in the methods, uses, and combination therapies disclosed herein is an interleukin such as human interleukins IL-2, IL- 7, IL-10, IL-12, IL-15, or a combination thereof.
  • the interleukin is IL-2, IL-7, IL-10, IL-12, or a combination thereof.
  • the interleukin is IL-2, IL-12, IL-15, or a combination thereof.
  • the interleukin is IL-2. In another embodiment, the interleukin is IL-7. In another embodiment, the interleukin is IL- 10. In another embodiment, the interleukin is IL-15. In a particular embodiment, the interleukin is IL-12. In certain other particular embodiments, the cytokine employed in the methods, uses, and combination therapies disclosed herein is an interleukin that is fused to a protein to form a fusion protein, such as IL-12 fused to collagen-binding lumican.
  • the cytokine employed in the methods, uses, and combination therapies disclosed herein is an interleukin that is fused to a protein to form a fusion protein, such as IL-2 fused to collagen-binding lumican.
  • IL-12 or IL-2 fused to lumican are described in PCT publication WO 2020/068261, which is incorporated herein by reference.
  • Compound A is used in the methods, uses, and combination therapies disclosed here in combination with the cytokine IL-12 fused to lumican. 5.
  • FIG.1 shows the anti-tumor effect of a triple combination of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and a cytokine (IL- 2, IL-12, or IL-15) in a mouse model.
  • Panel A of FIG.1 shows primary and distal tumor growth over time. Data is shown as mean ⁇ SEM.
  • Panel B of FIG.1 shows survival of the mice over time.
  • FIG.2 shows the anti-tumor effect of a triple combination of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and a cytokine (IL-7 or IL-10) in a mouse model.
  • FIG.3A, 3B, and 3C show the anti-tumor effect of a triple combination of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and various doses of IL-12 (50 ng for FIG.3A, 200 ng for FIG.3B, and 1 ⁇ g for FIG.3C) in a mouse model.
  • Panel A of each of FIGs.3A, 3B, and 3C shows primary and distal tumor growth over time.
  • Panel B of each of FIGs.3A, 3B, and 3C shows survival of the mice over time.
  • FIG.4 shows the anti-tumor effect of a triple combination of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and various doses of IL-12 (3 ng, 10 ng, or 30 ng) in a mouse model.
  • Panel A of FIG.4 shows primary and distal tumor growth over time.
  • Panel B of FIG.4 shows survival of the mice over time.
  • Panel C of FIG.4 shows mouse body weight change over time.
  • Data in panels A and C is shown as mean ⁇ SEM.
  • FIG.5 shows the anti-tumor effect of combinations of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and IL-12-Fc in a mouse model.
  • Panel A of FIG.5 shows primary and distal tumor growth over time.
  • Panel B of FIG.5 shows survival of the mice over time.
  • Panel C of FIG.5 shows the body weight change over time. Data in panels A and C is shown as mean ⁇ SEM.
  • FIG.6 shows the anti-tumor effect of a triple combination of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and various doses of IL-12-Fc (5 ng, 17 ng, or 50 ng) in a mouse model.
  • FIG.7 shows the anti-tumor effect of a triple combination of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and interleukins IL- 12-Fc (30 ng) or IL12-MSA-Lumican (20 ng, 60 ng, or 200 ng) in a mouse model.
  • Panel A of FIG.7 shows primary and distal tumor growth over time.
  • Panel B of FIG.7 shows survival of the mice over time.
  • FIG.7 shows mouse body weight change over time. Data in panels A and C is shown as mean ⁇ SEM.
  • FIG.8 shows the anti-tumor effect of various combinations of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and interleukin IL12-MSA-Lumican in a mouse model. Panel A of FIG.8 shows primary and distal tumor growth over time. Panel B of FIG.8 shows survival of the mice over time. Data in panel A is shown as mean ⁇ SEM.
  • FIG.9 shows the tumor growth in na ⁇ ve mice or in mice previously treated with a triple combination of a STING agonist (Compound A), an immune checkpoint inhibitor (anti-PD-L1 antibody), and interleukin IL12-MSA-Lumican (20 ng, 60 ng, or 200 ng).
  • Compound A a STING agonist
  • anti-PD-L1 antibody an immune checkpoint inhibitor
  • interleukin IL12-MSA-Lumican 20 ng, 60 ng, or 200 ng.
  • a combination therapy for treating tumors in a cancer patient disclosed herein comprising a STING agonist and a cytokine, wherein both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, would comprise intratumoral administration regimens for each of the STING agonist and the cytokine in sufficient dosing and frequency to treat tumors in the cancer patient.
  • “Conjointly administering” refers herein to any form of administration of two or more different therapeutic compounds such that the second administered compound is administered while the first administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include additive or synergistic effects of the two compounds).
  • a STING agonist and a cytokine as disclosed herein can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially.
  • the STING agonist and the cytokine disclosed herein can be administered within 1 hour, 2 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • the STING agonist is administered first, and in other embodiments the cytokine is administered first.
  • an individual who receives such treatment can benefit from a combined effect of the different therapeutic compounds.
  • Effective amount refers to an amount of the stated substance (e.g., a STING agonist, cytokine, or immune checkpoint inhibitor as disclosed herein) that is sufficient, when combined with another stated substance (e.g., a STING agonist, cytokine, or immune checkpoint inhibitor as disclosed herein) to treat the stated disease, disorder, or condition or have the desired stated effect on the disease, disorder, or condition or on one or more mechanisms underlying the disease, disorder, or condition or have the desired stated biological effect (e.g., augmenting anti-tumor response, increasing the population or function of immune cells, or increasing proliferation or function of tumor infiltrating leukocytes) in a human subject, such as a cancer patient.
  • a human subject such as a cancer patient.
  • effective amounts refers to both an amount of the STING agonist and an amount of the cytokine (and an amount of the checkpoint inhibitor) which, upon conjoint administration to a human, treats, or ameliorates tumors in the human, or exhibits a detectable therapeutic or biological effect in the human.
  • the therapeutic effect can be detected by, for example, a reduction in the size of one or more tumors, reduction in the proliferation of tumors, and increased survival times.
  • the biological effect can be assessed by measuring the numbers of tumor infiltrating leukocytes using their surface markers such as CD45, determining the populations of specific immune cells including but not limited to T cells, NK cells, B cells, dendritic cells, or macrophages in tumor biopsies and in the blood, as well as measuring gene expression in single cells as well as in bulk cells in the tumors.
  • the biological effect and safety of the therapies can also be examined by measuring a variety of inflammatory cytokines in the tumors and in the blood, by body weight and body temperature measurements, and by standard clinical and anatomical assessments as deemed necessary and appropriate by licensed clinicians.
  • “Reducing recurrence of tumors” or “preventing recurrence of tumors” in a cancer patient as used herein refers to reducing or preventing the recurrence of tumors in a cancer patient, who has been administered the specified agents (e.g., STING agonist, cytokine, and preferably with the optional immune checkpoint inhibitor), relative to a similarly afflicted cancer patient or patient type, who has not been administered the specified agents.
  • the reduction or prevention in recurrence of tumors occurs even when the patient does not receive further treatment with the specified agents.
  • treatment with the specified agents in addition to treating existing cancer/tumors, augments the anti-tumor response of the patient’s immune system so as to reduce or prevent recurrence of tumors in the future after treatment with the specified agents has ended.
  • Treatment refers to therapeutic applications associated with conjointly administering a STING agonist and a cytokine (and preferably but optionally with an immune checkpoint inhibitor) as disclosed herein that ameliorate the indicated disease, disorder, or condition or one or more underlying mechanisms of said disease, disorder, or condition, including slowing or stopping progression of the disease, disorder, or condition or one or more of the underlying mechanisms in a human subject, such as a cancer patient.
  • treatment refers to therapeutic applications to slow or stop progression of the tumors or the cancer and/or reversal of the tumors or the cancer.
  • Reversal of tumors or the cancer differs from a therapeutic application that slows or stops tumors or the cancer in that with a method of reversing, not only is progression of the tumors or the cancer stopped, cellular behavior is moved to some degree toward a normal state that would be observed in the absence of the tumors or the cancer.
  • the disclosure provides methods of treating a disease or disorder, particularly cancer, in a patient in need thereof, such as a method of treating tumors in a cancer patient in need thereof, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • the patient is currently receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • Conjoint administration contemplates that the STING agonist can be administered simultaneously, prior to, or after administration of the cytokine.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient and wherein the patient exhibits reduced recurrence of the tumors following treatment.
  • the patient is currently receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • Conjoint administration contemplates that the STING agonist can be administered simultaneously, prior to, or after administration of the cytokine.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • the patient is currently receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • Conjoint administration contemplates that the STING agonist can be administered simultaneously, prior to, or after administration of the cytokine.
  • the disclosure provides a method of augmenting the anti-tumor response of a cancer patient, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • the patient is currently receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • the augmented anti-tumor response can be shown, for example, by shrinkage of one or more tumors or by increased survival times.
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • the patient is currently receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • such methods increase the population or function of T cells.
  • such methods increase the population or function of NK cells.
  • such methods increase the population or function of B cells. In other embodiments, such methods increase the population or function of dendritic cells. In other embodiments, such methods increase the population or function of macrophages. As discussed herein, the increased population or function of immune cells can be shown, for example, by determining the populations of specific immune cells including but not limiting to T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof in tumor biopsies and in the blood.
  • the disclosure provides a method of increasing proliferation or function of tumor infiltrating leukocytes in a cancer patient, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient.
  • the patient is currently receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • the increased proliferation or function of tumor infiltrating leukocytes can be shown, for example, by measuring the numbers of tumor infiltrating leukocytes using their surface markers such as CD45.
  • the STING agonist and the cytokine can both be administered intratumorally to a patient.
  • the STING agonist and the cytokine can be administered together in the same pharmaceutical composition or in separate pharmaceutical compositions.
  • the cytokine can be administered intratumorally to the patient, and the STING agonist can be administered systemically (e.g., intravenously, intramuscularly, subcutaneously, or orally) to the patient.
  • the cytokine can be administered intratumorally to the patient, and the STING agonist can be administered intravenously to the patient.
  • the cytokine can be administered intratumorally to the patient, and the STING agonist can be administered intramuscularly to the patient.
  • the cytokine can be administered intratumorally to the patient, and the STING agonist can be administered orally to the patient.
  • the STING agonist can be administered intratumorally to the patient, and the cytokine can be administered systemically (e.g., intravenously, intramuscularly, or subcutaneously) to the patient.
  • the STING agonist can be administered intratumorally to the patient, and the cytokine can be administered intravenously to the patient.
  • the STING agonist can be administered intratumorally to the patient, and the cytokine can be administered intramuscularly to the patient. In particular embodiments, the STING agonist can be administered intratumorally to the patient, and the cytokine can be administered subcutaneously to the patient.
  • the method is a method of treating tumors in a cancer patient in need thereof. In certain embodiments, the method is a method of reducing recurrence of tumors in a cancer patient in need thereof. In certain embodiments, the method is a method of preventing recurrence of tumors in a cancer patient in need thereof. In certain embodiments, the method is a method of augmenting the anti-tumor response of a cancer patient.
  • the method is a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient.
  • immune cells such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof.
  • the two compositions can be administered concomitantly or sequentially.
  • the STING agonist can be administered prior to the administration of the cytokine.
  • the STING agonist can be administered after administration of the cytokine.
  • the STING agonist and the cytokine can be administered in combination, e.g., conjointly, without any additional therapeutic agents.
  • the combination of STING agonist and cytokine provides sufficient tumor inhibition such that additional chemotherapeutic agents or immunotherapeutic agents may not provide additional tumor inhibition.
  • the STING agonist and the cytokine are administered in combination with one or more additional anti-cancer agents, such as in combination with an immune checkpoint inhibitor, such as a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor, including an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.
  • an immune checkpoint inhibitor such as a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor, including an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody.
  • the immune checkpoint inhibitor is an anti- PD-L1 antibody.
  • the immune checkpoint inhibitor is an anti-CTLA- 4 antibody.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient, and further comprising administering in combination (e.g., conjointly) an effective amount of an immune checkpoint inhibitor to the patient.
  • the immune checkpoint inhibitor is intratumorally administered to the patient.
  • the immune checkpoint inhibitor is administered systemically (e.g., intravenously, intramuscularly, or subcutaneously) to the patient.
  • the immune checkpoint inhibitor is intravenously administered.
  • the immune checkpoint inhibitor is intramuscularly administered.
  • the immune checkpoint inhibitor is subcutaneously administered.
  • the patient is receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient, and further comprising administering in combination (e.g., conjointly) an effective amount of an immune checkpoint inhibitor to the patient and wherein the patient exhibits reduced recurrence of the tumors following treatment.
  • the immune checkpoint inhibitor is intratumorally administered to the patient.
  • the immune checkpoint inhibitor is administered systemically (e.g., intravenously, intramuscularly, or subcutaneously) to the patient.
  • the immune checkpoint inhibitor is intravenously administered.
  • the immune checkpoint inhibitor is intramuscularly administered.
  • the immune checkpoint inhibitor is subcutaneously administered.
  • the patient is receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • the methods and uses described herein comprise conjointly administering effective amounts of a STING agonist, a cytokine, and an immune checkpoint inhibitor to the patient, wherein the STING agonist and the cytokine are intratumorally administered to the patient and the immune checkpoint inhibitor is systematically administered to the patient and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.
  • the method is a method of treating tumors in a cancer patient in need thereof.
  • the method is a method of reducing recurrence of tumors in a cancer patient in need thereof.
  • the method is a method of preventing recurrence of tumors in a cancer patient in need thereof. In certain embodiments, the method is a method of augmenting the anti-tumor response of a cancer patient. In certain embodiments, the method is a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient.
  • immune cells such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof
  • the methods and uses described herein comprise conjointly administering effective amounts of a STING agonist, a cytokine, and an immune checkpoint inhibitor to the patient, wherein the STING agonist and the cytokine are intratumorally administered to the patient and the immune checkpoint inhibitor is systematically administered to the patient and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody and wherein the STING agonist is a cyclic dinucleotide (CDN).
  • the immune checkpoint inhibitor is an anti-PD- 1 antibody.
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody.
  • the immune checkpoint inhibitor is an anti-CTLA-4 antibody.
  • the method is a method of treating tumors in a cancer patient in need thereof. In certain embodiments, the method is a method of reducing recurrence of tumors in a cancer patient in need thereof. In certain embodiments, the method is a method of preventing recurrence of tumors in a cancer patient in need thereof. In certain embodiments, the method is a method of augmenting the anti-tumor response of a cancer patient. In certain embodiments, the method is a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient.
  • immune cells such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof
  • the methods and uses described herein comprise conjointly administering effective amounts of a STING agonist, a cytokine, and an immune checkpoint inhibitor to the patient, wherein the STING agonist and the cytokine are intratumorally administered to the patient and the immune checkpoint inhibitor is systematically administered to the patient and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody, and wherein the cytokine is an interleukin, and wherein the STING agonist is a cyclic dinucleotide (CDN).
  • the immune checkpoint inhibitor is an anti-PD-1 antibody.
  • the immune checkpoint inhibitor is an anti-PD-L1 antibody.
  • the immune checkpoint inhibitor is an anti-CTLA-4 antibody.
  • the method is a method of treating tumors in a cancer patient in need thereof.
  • the interleukin is IL-12, such as a fusion protein of IL-12, such as IL-12-Fc or IL-12-MSA-lumican.
  • the method is a method of reducing recurrence of tumors in a cancer patient in need thereof.
  • the method is a method of preventing recurrence of tumors in a cancer patient in need thereof.
  • the method is a method of augmenting the anti-tumor response of a cancer patient.
  • the method is a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) of a cancer patient.
  • the disclosure provides a method of treating of tumors in a cancer patient in need thereof, comprising causing a STING agonist, a cytokine, and an immune checkpoint inhibitor to be concurrently present in the patient’s body.
  • the method comprises administering an effective amount of the STING agonist to the patient, wherein the patient has already been administered the cytokine and the immune checkpoint inhibitor.
  • the method comprises administering an effective amount of the cytokine to the patient, wherein the patient has already been administered the STING agonist and the immune checkpoint inhibitor. In some embodiments, the method comprises administering an effective amount of the immune checkpoint inhibitor to the patient, wherein the patient has already been administered the STING agonist and the cytokine. [0062] In some embodiments, the disclosure provides a method of reducing recurrence of tumors in a patient, comprising causing a STING agonist, a cytokine, and an immune checkpoint inhibitor to be concurrently present in the patient’s body.
  • the method comprises administering an effective amount of the STING agonist to the patient, wherein the patient has already been administered the cytokine and the immune checkpoint inhibitor. In some embodiments, the method comprises administering an effective amount of the cytokine to the patient, wherein the patient has already been administered the STING agonist and the immune checkpoint inhibitor. In some embodiments, the method comprises administering an effective amount of the immune checkpoint inhibitor to the patient, wherein the patient has already been administered the STING agonist and the cytokine.
  • the disclosure provides a method of preventing recurrence of tumors in a patient, comprising causing a STING agonist, a cytokine, and an immune checkpoint inhibitor to be concurrently present in the patient’s body.
  • the method comprises administering an effective amount of the STING agonist to the patient, wherein the patient has already been administered the cytokine and the immune checkpoint inhibitor.
  • the method comprises administering an effective amount of the cytokine to the patient, wherein the patient has already been administered the STING agonist and the immune checkpoint inhibitor.
  • the method comprises administering an effective amount of the immune checkpoint inhibitor to the patient, wherein the patient has already been administered the STING agonist and the cytokine.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA- 4 antibody to the cancer patient.
  • the STING agonist is a CDN and/or the cytokine is an interleukin.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient and wherein the patient exhibits reduced recurrence of the tumors following treatment.
  • an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody
  • the STING agonist is a CDN.
  • the cytokine is an interleukin, such as IL-12, such as a fusion protein of IL-12, such as IL-12-Fc or IL-12- MSA-lumican.
  • the STING agonist is a CDN, and the cytokine is an interleukin, such as IL-12, such as a fusion protein of IL-12, such as IL-12- Fc or IL-12-MSA-lumican.
  • the patient exhibits reduced recurrence of the tumors following treatment.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • the STING agonist is a CDN.
  • the cytokine is an interleukin, such as IL-12, such as a fusion protein of IL-12, such as IL-12-Fc or IL-12- MSA-lumican.
  • the STING agonist is a CDN
  • the cytokine is an interleukin, such as IL-12, such as a fusion protein of IL-12, such as IL-12- Fc or IL-12-MSA-lumican.
  • the patient exhibits reduced recurrence of the tumors following treatment.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is a CDN and a cytokine that is IL-12 to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist, a cytokine, and an immune checkpoint inhibitor to the patient, wherein the STING agonist and the cytokine are intratumorally administered to the cancer patient, and the immune checkpoint inhibitor is systemically administered to the patient; and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is a CDN, a cytokine that is IL-12, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the patient, wherein both the CDN and the IL-12 are administered intratumorally to the patient, and the immune checkpoint inhibitor is intravenously administered to the patient.
  • the IL-12 is a fusion protein of IL-12, such as IL-12-Fc or IL-12-MSA-lumican.
  • the patient exhibits reduced recurrence of the tumors following treatment.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is Compound A, a cytokine, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient, wherein both the Compound A and the cytokine are administered intratumorally to the patient, and the immune checkpoint inhibitor is intravenously administered to the patient.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment. In certain of such particular embodiments, the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment. In certain of such particular embodiments, the cytokine is fused to a collagen-binding protein, such as lumican. In certain of such particular embodiments, the cytokine is fused to an immunoglobulin Fc domain. In a particular embodiment, the patient exhibits reduced recurrence of the tumors following treatment.
  • the disclosure provides a method of treating tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is a CDN and a cytokine that is IL-12 to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient and wherein the patient exhibits reduced recurrence of the tumors following treatment.
  • a STING agonist that is a CDN
  • a cytokine that is IL-12
  • the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient and wherein the patient exhibit
  • the IL-12 is a fusion protein of IL-12, such as IL-12-Fc or IL-12-MSA-lumican.
  • the disclosure provides a method of augmenting the anti-tumor response in a cancer patient, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient, and further comprising administering in combination (e.g., conjointly) an effective amount of an immune checkpoint inhibitor to the patient.
  • the immune checkpoint inhibitor is intratumorally administered to the patient.
  • the immune checkpoint inhibitor is administered systemically (e.g., intravenously, intramuscularly, or subcutaneously) to the patient.
  • the immune checkpoint inhibitor is intravenously administered.
  • the immune checkpoint inhibitor is intramuscularly administered.
  • the immune checkpoint inhibitor is subcutaneously administered.
  • the patient is receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • the disclosure provides a method of augmenting the anti- tumor response in a cancer patient, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA- 4 antibody to the cancer patient.
  • the STING agonist is a CDN and/or the cytokine is an interleukin.
  • the disclosure provides a method of augmenting the anti- tumor response in a cancer patient, comprising conjointly administering effective amounts of a STING agonist that is a CDN and a cytokine that is IL-12 to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • a STING agonist that is a CDN
  • a cytokine that is IL-12
  • both the STING agonist and the cytokine are administered intratumorally to the patient
  • the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer
  • the disclosure provides a method of augmenting the anti- tumor response in a cancer patient, comprising conjointly administering effective amounts of a STING agonist, a cytokine, and an immune checkpoint inhibitor to the patient, wherein the STING agonist and the cytokine are intratumorally administered to the patient, and the immune checkpoint inhibitor is systemically administered to the patient; and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.
  • the disclosure provides a method of augmenting the anti- tumor response in a cancer patient, comprising conjointly administering effective amounts of a STING agonist that is a CDN, a cytokine that is IL-12, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the patient, wherein both the CDN and the IL-12 are administered intratumorally to the patient, and the immune checkpoint inhibitor is intravenously administered to the patient.
  • the IL-12 is a fusion protein of IL-12, such as IL-12-Fc or IL-12-MSA-lumican.
  • the disclosure provides a method of augmenting the anti-tumor response in a cancer patient, comprising conjointly administering effective amounts of a STING agonist that is Compound A, a cytokine, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient, wherein both the Compound A and the cytokine are administered intratumorally to the patient, and the immune checkpoint inhibitor is intravenously administered to the patient.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment.
  • the cytokine is fused to a collagen-binding protein such as lumican.
  • the cytokine is fused to an immunoglobulin Fc domain.
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) in a cancer patient, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient, and further comprising administering in combination (e.g., conjointly) an effective amount of an immune checkpoint inhibitor to the patient.
  • the immune checkpoint inhibitor is intratumorally administered to the patient.
  • the immune checkpoint inhibitor is administered systemically (e.g., intravenously, intramuscularly, or subcutaneously) to the patient.
  • the immune checkpoint inhibitor is intravenously administered.
  • the immune checkpoint inhibitor is intramuscularly administered.
  • the immune checkpoint inhibitor is subcutaneously administered.
  • the patient is receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • such methods increase the population or function of T cells.
  • such methods increase the population or function of NK cells.
  • such methods increase the population or function of B cells.
  • dendritic cells are examples of dendritic cells.
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) in a cancer patient, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • the STING agonist is a CDN and/or the cytokine is an interleukin.
  • such methods increase the population or function of T cells.
  • such methods increase the population or function of NK cells.
  • such methods increase the population or function of B cells.
  • such methods increase the population or function of dendritic cells.
  • such methods increase the population or function of macrophages.
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) in a cancer patient, comprising conjointly administering effective amounts of a STING agonist that is a CDN and a cytokine that is IL- 12 to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • such methods increase the population or function of T cells. In other embodiments, such methods increase the population or function of NK cells. In other embodiments, such methods increase the population or function of B cells. In other embodiments, such methods increase the population or function of dendritic cells. In other embodiments, such methods increase the population or function of macrophages.
  • the disclosure provides a method of increasing the population or function of immune cells (such as T cells, NK cells, B cells, dendritic cells, or macrophages, or a combination thereof) in a cancer patient, comprising conjointly administering effective amounts of a STING agonist, a cytokine, and an immune checkpoint inhibitor to the patient, wherein the STING agonist and the cytokine are intratumorally administered to the patient, and the immune checkpoint inhibitor is systemically administered to the patient; and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.
  • such methods increase the population or function of T cells.
  • such methods increase the population or function of NK cells. In other embodiments, such methods increase the population or function of B cells. In other embodiments, such methods increase the population or function of dendritic cells. In other embodiments, such methods increase the population or function of macrophages.
  • the disclosure provides a method of augmenting the anti- tumor response in a cancer patient, comprising conjointly administering effective amounts of a STING agonist that is a CDN, a cytokine that is IL-12, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the patient, wherein both the CDN and the IL-12 are administered intratumorally to the patient, and the immune checkpoint inhibitor is intravenously administered to the cancer patient.
  • the IL-12 is a fusion protein of IL-12, such as IL-12- Fc or IL-12-MSA-lumican.
  • such methods increase the population or function of T cells. In other embodiments, such methods increase the population or function of NK cells. In other embodiments, such methods increase the population or function of B cells. In other embodiments, such methods increase the population or function of dendritic cells. In other embodiments, such methods increase the population or function of macrophages.
  • the disclosure provides a method of augmenting the anti-tumor response in a cancer patient, comprising conjointly administering effective amounts of a STING agonist that is Compound A, a cytokine, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient, wherein both the Compound A and the cytokine are administered intratumorally to the cancer patient, and the immune checkpoint inhibitor is intravenously administered to the patient.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment.
  • the cytokine is fused to a collagen-binding protein such as lumican.
  • the cytokine is fused to an immunoglobulin Fc domain.
  • such methods increase the population or function of T cells.
  • such methods increase the population or function of NK cells.
  • such methods increase the population or function of B cells.
  • such methods increase the population or function of dendritic cells.
  • such methods increase the population or function of macrophages.
  • the disclosure provides a method of increasing proliferation or function of tumor infiltrating leukocytes in a cancer patient, comprising conjointly administering in combination (e.g., conjointly) a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient, and further comprising administering in combination (e.g., conjointly) an effective amount of an immune checkpoint inhibitor to the patient.
  • the immune checkpoint inhibitor is intratumorally administered to the patient.
  • the immune checkpoint inhibitor is administered systemically (e.g., intravenously, intramuscularly, or subcutaneously) to the patient.
  • the immune checkpoint inhibitor is intravenously administered.
  • the disclosure provides a method of increasing proliferation or function of tumor infiltrating leukocytes in a cancer patient, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • the STING agonist is a CDN and/or the cytokine is an interleukin.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment.
  • the cytokine is fused to a collagen-binding protein such as lumican.
  • the cytokine is fused to an immunoglobulin Fc domain.
  • the disclosure provides a method of increasing proliferation or function of tumor infiltrating leukocytes in a cancer patient, comprising conjointly administering effective amounts of a STING agonist that is a CDN and a cytokine that is IL-12 to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA- 4 antibody to the cancer patient.
  • a STING agonist that is a CDN
  • a cytokine that is IL-12
  • the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA- 4 antibody to the cancer patient.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment. In certain of such particular embodiments, the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment. In certain of such particular embodiments, the cytokine is fused to a collagen-binding protein such as lumican. In certain of such particular embodiments, the cytokine is fused to an immunoglobulin Fc domain.
  • the disclosure provides methods of treating or preventing metastasis in a human cancer patient comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient, and optionally further comprising administering in combination (e.g., conjointly) an effective amount of an immune checkpoint inhibitor to the patient.
  • the methods can be used to treat primary or metastasizing tumors that are resistant to immune checkpoint therapy.
  • the STING agonist and the cytokine are conjointly administered with a PD-1, PD-L1, or CTLA-4 inhibitor, or the cancer patient is currently receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment.
  • the cytokine is fused to a collagen- binding protein such as lumican.
  • the cytokine is fused to an immunoglobulin Fc domain.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising administering in combination (e.g., conjointly) effective amounts of a STING agonist and a cytokine to the patient, wherein the STING agonist or the cytokine is intratumorally administered to the patient, and further comprising administering in combination (e.g., conjointly) an effective amount of an immune checkpoint inhibitor to the patient.
  • the immune checkpoint inhibitor is intratumorally administered to the patient.
  • the immune checkpoint inhibitor is administered systemically (e.g., intravenously, intramuscularly, or subcutaneously) to the patient.
  • the immune checkpoint inhibitor is intravenously administered.
  • the immune checkpoint inhibitor is intramuscularly administered.
  • the immune checkpoint inhibitor is subcutaneously administered.
  • the patient is receiving an immune checkpoint inhibitor as part of anti-tumor therapy.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • the STING agonist is a CDN.
  • the cytokine is an interleukin, such as IL-12, such as a fusion protein of IL-12, such as IL-12-Fc or IL-12- MSA-lumican.
  • the STING agonist is a CDN and the cytokine is an interleukin, such as IL-12, such as a fusion protein of IL-12, such as IL-12- Fc or IL-12-MSA-lumican.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is a CDN and a cytokine that is IL-12 to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • a STING agonist that is a CDN
  • a cytokine that is IL-12
  • the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is a CDN and a cytokine to the patient, wherein both the STING agonist and the cytokine are administered intratumorally to the patient, and the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • a STING agonist that is a CDN and a cytokine
  • both the STING agonist and the cytokine are administered intratumorally to the patient
  • the method further comprises conjointly systemically (e.g., intravenously) administering an effective amount of an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody to the cancer patient.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment. In certain of such particular embodiments, the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment. In certain of such particular embodiments, the cytokine is fused to a collagen-binding protein such as lumican. In certain of such particular embodiments, the cytokine is fused to an immunoglobulin Fc domain.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is a CDN, a cytokine that is IL-12, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA- 4 antibody to the patient, wherein both the CDN and the IL-12 are administered intratumorally to the patient, and the immune checkpoint inhibitor is intravenously administered to the patient.
  • the IL-12 is a fusion protein of IL-12, such as IL-12-Fc or IL-12-MSA-lumican.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist, a cytokine, and an immune checkpoint inhibitor to the patient, wherein the STING agonist and the cytokine are intratumorally administered to the cancer patient, and the immune checkpoint inhibitor is systemically administered to the patient; and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.
  • the disclosure provides a method of reducing recurrence of tumors in a cancer patient in need thereof, comprising conjointly administering effective amounts of a STING agonist that is Compound A, a cytokine, and an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA- 4 antibody to the cancer patient, wherein both the Compound A and the cytokine are administered intratumorally to the patient, and the immune checkpoint inhibitor is intravenously administered to the patient.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is an antibody or an antibody fragment.
  • the cytokine is fused to a protein to form a fused protein, wherein the protein is not an antibody or an antibody fragment. In certain of such particular embodiments, the cytokine is fused to a collagen- binding protein such as lumican. [0096] In some embodiments, the disclosure provides a mixture comprising a STING agonist, a cytokine, and an immune checkpoint inhibitor. In some embodiments the mixture further comprises human plasma. [0097] In particular embodiments, the disclosure provides a mixture comprising a STING agonist that is a CDN, a cytokine, an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody, and human plasma.
  • the disclosure provides a mixture comprising a STING agonist that is a CDN, a cytokine that is an interleukin, an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody, and human plasma.
  • a STING agonist that is Compound A a cytokine that is an interleukin (such as IL-12), an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody, and human plasma.
  • the IL- 12 is a fusion protein of IL-12, such as IL-12-Fc or IL-12-MSA-lumican [0098]
  • the STING agonist and the cytokine can be administered to a cancer patient in combination, e.g., conjointly, with a PD-1, PD-L1, or CTLA-4 inhibitor, such as those described herein.
  • the PD-1, PD-L1, or CTLA-4 inhibitor can be administered simultaneously with, prior to or after administration of the STING agonist and/or the cytokine.
  • the PD-1, PD-L1, or CTLA-4 inhibitor can be administered intratumorally.
  • the PD-1, PD-L1, or CTLA-4 inhibitor can be administered systemically, such as intravenously, subcutaneously, or intramuscularly.
  • both the STING agonist and the cytokine are administered intratumorally to the cancer patient, and the PD-1, PD-L1, or CTLA-4 inhibitor is administered systemically, such as intravenously, subcutaneously, or intramuscularly.
  • the cytokine is administered intratumorally to the cancer patient, and both the STING agonist and the PD-1, PD-L1, or CTLA-4 inhibitor are administered systemically, such as intravenously, subcutaneously, intramuscularly, or orally.
  • the STING agonist is administered intratumorally to the cancer patient, and both the cytokine and the PD-1, PD-L1, or CTLA-4 inhibitor are administered systemically, such as intravenously, subcutaneously, or intramuscularly.
  • both the cytokine and the PD-1, PD-L1, or CTLA-4 inhibitor are administered intratumorally to the cancer patient, and the STING agonist is administered systemically, such as intravenously, subcutaneously, intramuscularly, or orally.
  • both the STING agonist and the PD-1, PD-L1, or CTLA-4 inhibitor are administered intratumorally to the cancer patient, and the cytokine is administered systemically, such as intravenously, subcutaneously, or intramuscularly.
  • the STING agonist, the cytokine, and the PD-1, PD-L1, or CTLA-4 inhibitor are all administered intratumorally to the cancer patient.
  • the STING agonist and the cytokine are administered in combination, e.g., conjointly, with a CTLA-4 inhibitor and either a PD-1 inhibitor or a PD-L1 inhibitor.
  • the CTLA-4 inhibitor is an anti-CTLA-4 antibody that is either intratumorally or systemically administered, particularly intratumorally administered.
  • the methods and uses described herein upon administration of the STING agonist and the cytokine and optionally the immune checkpoint inhibitor, produce an abscopal effect in tumors distal to the site of intratumoral administration of the STING agonist or the cytokine.
  • the method and uses herein treat tumors distal to the site of intratumoral administration of the STING agonist and/or the cytokine.
  • the method and uses herein treat tumors distal to the site of intratumoral administration of the STING agonist.
  • the method and uses herein treat tumors distal to the site of intratumoral administration of the STING agonist and/or the cytokine.
  • the STING agonist and cytokine are administered to a cancer patient already receiving immune checkpoint inhibition therapy, such as for whom the tumor or cancer has stabilized.
  • the cancer patient has undergone at least 1 or 2 cycles of immune checkpoint inhibitor therapy prior to administration of the STING agonist and the cytokine.
  • the cancer patient may have undergone 2, 3, 4, 5, 6, 7, or 8 cycles of immune checkpoint inhibition therapy prior to administration of the STING agonist and the cytokine.
  • the cancer patient continues to receive immune checkpoint inhibition therapy with successive cycles of the STING agonist and cytokine.
  • the present disclosure provides a combination therapy, such as for treating tumors in a cancer patient in need thereof, comprising a STING agonist and a cytokine, wherein the STING agonist or the cytokine is formulated for intratumoral administration to the patient.
  • both the STING agonist and the cytokine are formulated for intratumoral administration to the patient.
  • the cytokine is formulated for intratumoral administration
  • the STING agonist is formulated for systemic administration to the patient, such as for intravenous, subcutaneous, intramuscular, or oral administration.
  • the STING agonist is formulated for intravenous administration. In certain embodiments, the STING agonist is formulated for subcutaneous administration. In certain embodiments, the STING agonist is formulated for intramuscular administration. In certain embodiments, the STING agonist is formulated for oral administration. In other embodiments, STING agonist is formulated for intratumoral administration, and the cytokine is formulated for systemic administration to the patient, such as for intravenous, subcutaneous, or intramuscular administration. In certain embodiments, the cytokine is formulated for intravenous administration. In certain embodiments, the cytokine is formulated for subcutaneous administration. In certain embodiments, the cytokine is formulated for intramuscular administration.
  • the disclosure provides a combination therapy, such as for treating tumors in a cancer patient in need thereof, wherein both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the combination therapy further comprises an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody formulated for systemic administration to the cancer patient.
  • the STING agonist is a CDN and/or the cytokine is an interleukin.
  • the disclosure provides a combination therapy for treating tumors in a cancer patient in need thereof, wherein the STING agonist is a CDN and the cytokine is IL-12, and both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the combination therapy further comprises an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody formulated for systemic administration to the cancer patient.
  • the combination therapies disclosed herein further comprise an immune checkpoint inhibitor.
  • the combination therapies disclosed herein further comprise an immune checkpoint inhibitor, such as a PD-1, PD-L1, or CTLA-4 inhibitor (such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody).
  • the immune checkpoint inhibitor is an anti-PD-1 antibody.
  • the immune checkpoint inhibitor is an anti- PD-L1antibody.
  • the immune checkpoint inhibitor is an CTLA-4 antibody.
  • the immune checkpoint inhibitor is formulated for intratumoral administration to the cancer patient.
  • the immune checkpoint inhibitor is formulated for systemic administration to the cancer patient, such as for intravenous, subcutaneous, or intramuscular administration.
  • the immune checkpoint inhibitor is formulated for intravenous administration. In certain embodiments, the immune checkpoint inhibitor is formulated for subcutaneous administration. In certain embodiments, the immune checkpoint inhibitor is formulated for intramuscular administration. [00106] In a particular embodiment, the disclosure provides a combination therapy, such as for treating tumors in a cancer patient in need thereof, wherein the STING agonist or the cytokine are formulated for intratumoral administration to the patient, and the combination therapy further comprises an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody formulated for systemic administration to the cancer patient.
  • the disclosure provides a combination therapy, such as for treating tumors in a cancer patient in need thereof, wherein both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the combination therapy further comprises an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody formulated for systemic administration to the cancer patient.
  • a combination therapy such as for treating tumors in a cancer patient in need thereof, wherein both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the combination therapy further comprises an immune checkpoint inhibitor that is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody formulated for systemic administration to the cancer patient.
  • the present disclosure provides a combination therapy, such as for treating tumors in a cancer patient in need thereof, comprising a STING agonist, a cytokine, and an immune checkpoint inhibitor, wherein the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the immune checkpoint inhibitor is formulated for systemic administration to the patient; and the immune checkpoint inhibitor is an anti-PD-1 antibody, and anti-PD-L1 antibody, or an anti-CTLA-4 antibody.
  • the disclosure provides a combination therapy for treating tumors in a cancer patient in need thereof, wherein the STING agonist is a CDN, the cytokine is an interleukin, and both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the immune checkpoint inhibitor is an anti- PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody and is formulated for systemic administration to the cancer patient.
  • the STING agonist is Compound A.
  • the cytokine is an interleukin that is IL-12.
  • the disclosure provides a combination therapy for treating tumors in a cancer patient in need thereof, wherein the STING agonist is Compound A, the cytokine is IL-12, and both the STING agonist and the cytokine are formulated for intratumoral administration to the patient, and the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody and is formulated for systemic administration to the cancer patient.
  • the cytokine is fused to a protein to form a fusion protein.
  • the cytokine is fused to a protein to form a fusion protein, wherein the protein is an antibody or an antibody fragment.
  • the cytokine is fused to a protein to form a fusion protein, wherein the protein is not an antibody or an antibody fragment.
  • the STING agonist used in the methods, uses, combination therapies, and mixtures described herein is a cyclic dinucleotide (CDN) compound.
  • the STING agonist can be a 2’3’-CDN, such as 2’3’-cGAMP, Compound A, Compound B, or Compound C, depicted below, particularly Compound A.
  • the STING agonist is a 3’3’-CDN, a 2’2’-CDN, or a 3’2’-CDN, such as 3’3’- cGAMP, 2’2’-cGAMP, or 3’2’-cGAMP.
  • the STING agonist is a CDN that is an analog of 2’3’-cGAMP (i.e., a 2’3’-CDN that includes a guanine nucleobase and an adenine nucleobase), such as Compound A and Compound B, particularly Compound A.
  • the STING agonist is a benzophenone analog.
  • the STING agonist is a dimeric amidobenzimidazole.
  • STING agonists that can be used in accordance with the disclosure include ADU-S100 (MIW815), BMS-986301, CRD5500, CMA (10-carboxymethyl-9- acridanone), diABZI STING agonist-1 (e.g., CAS No.: 2138299-34-8), DMXAA (ASA404/vadimezan), E7766, GSK-532, GSK-3745417, MK-1454, MK-2118, SB-11285, SRCB-0074, TAK-676, TTI-10001, SR-717 and MSA-2.
  • the CDN used in the methods and combination therapies in accordance with the disclosure is the following compound (“Compound A”), or a pharmaceutically acceptable salt thereof: Compound A [00113]
  • Compound A can act both locally and systemically to exert a powerful ant-tumor effect.
  • Compound A when administered at particular dosages to a cancer patient in need thereof, is capable of substantially reducing or preventing the spreading of metastasis.
  • the ability of Compound A to reduce or prevent the onset and/or progression of metastasis can be potentiated when administered in combination, e.g., conjointly, with a cytokine, in accordance with the disclosure.
  • Compound A exerts a powerful abscopal effect when administered in combination with a cytokine, in accordance with the present disclosure.
  • Compound A can be administered over multiple cycles.
  • the first cycle comprises administering Compound A on days 1, 8, and 15 of a four-week period
  • subsequent cycles comprise administering Compound A on days 1 and 15 (i.e., biweekly) of a four-week period.
  • Compound A can be administered intratumorally or systemically, including subcutaneously, intramuscularly, or intravenously.
  • Compound A on days of the cycle designated for administration, Compound A can be administered at a dosage in the range of 50 ⁇ g to 6,500 ⁇ g. In some embodiments, on days of the cycle designated for administration, Compound A can be administered at a dosage in the range of 100 ⁇ g to 3,000 ⁇ g. In some embodiments, on days of the cycle designated for administration, Compound A can be administered at a dosage in the range of 100 ⁇ g to 1,200 ⁇ g.
  • the CDN used in the methods and combination therapies in accordance with the disclosure is the following compound (“Compound B”), or a pharmaceutically acceptable salt thereof: Compound B [00116] In another embodiment, the CDN used in the methods and combination therapies in accordance with the disclosure is the following compound (“Compound C”), or a pharmaceutically acceptable salt thereof:
  • the STING agonist used in the methods and combination therapies in accordance with the disclosure is a compound as disclosed in WO 2019/165032, which is herein incorporated by reference.
  • Such STING agonists can be administered orally, systemically, or intratumorally to the patient.
  • the STING agonist used in the methods and combination therapies in accordance with the disclosure is MSA-2 (“Compound E”), or a pharmaceutically acceptable salt thereof, which has the following structure: MSA-2 can be administered orally, systemically, or intratumorally to the patient.
  • CDNs that can be used as STING agonists in the present methods and combination therapies are disclosed in the following publications WO 2014/144666, WO 2014/179335, WO 2014/189806, WO 2015/161762, WO 2016/096174, WO 2017/027646, WO 2017/027645, WO 2017/161349, WO 2018/118664, WO 2018/118665, WO 2018/208667, WO2019/165032, and WO 2019/046511 the contents of each of which are incorporated by reference herein.
  • the STING agonist to be used in the methods and combination therapies in accordance with the disclosure can be conjugated to antibodies or antigen-binding fragments, hence producing antibody-drug conjugates (ADCs).
  • ADCs antibody-drug conjugates
  • the ADC to be administered in accordance with the methods and combination therapies disclosed herein has a structure as described in US 2017/0298139, WO 2017/100305, WO 2018/200812, or WO 2018/140831, the contents of each of which are herein incorporated by reference herein.
  • the ADC to be used in the methods and combination therapies in accordance with the disclosure has the structure of Formula IA: (IA) Ab-[-L-D] n wherein: “D” represents a CDN having the structure of Formula IIa:
  • R 1 is C 2-4 alkyl substituted with a thiol, amino, or C 1-6 alkylamino group
  • R p is, independently for each occurrence, hydroxyl, thiol, C 1-6 alkyl, borano (-BH3 ⁇ ), or –NR’R”, wherein R’ and R” are, independently for each occurrence, hydrogen or C 1-6 alkyl optionally substituted with one or more groups selected from halogen, thiol, hydroxyl, carboxyl, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, -OC(O)C 1- 6alkyl, -N(H)C(O)C 1-6 alkyl, -N(C 1-3 alkyl)C(O)C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, oxo, azido, and cyano;
  • the CDN of the ADC has he structure of Formula IIb: Formula IIb or a pharmaceutically acceptable salt thereof.
  • the STING agonist is part of an ADC of Formula IA
  • the CDN of the ADC has he structure of Formula IIc: Formula IIc or a pharmaceutically acceptable salt thereof.
  • the STING agonist is part of an ADC of Formula IA
  • the ADC has the structure of Formula III:
  • the ADC has the structure of Formula IV: Formula IV.
  • the ADC (“Compound F”) has the following structure: Compound F.
  • the ADC (“Compound G”) has the following structure: Compound G.
  • Examples of cytokines that can be used in the methods, uses, combination therapies, and mixtures disclosed herein include various interleukins, such as human interleukins IL-2, IL-7, IL-10, IL-12, IL-15, or a combination thereof.
  • the interleukin is IL-2, IL-7, IL-10, IL-12, or a combination thereof.
  • the interleukin is IL-2, IL-12, IL-15, or a combination thereof. In one embodiment, the interleukin is IL-2. In another embodiment, the interleukin is IL-7. In another embodiment, the interleukin is IL- 10. In another embodiment, the interleukin is IL-15. In a particular embodiment, the interleukin is IL-12. [00130] In certain embodiments, the interleukin is fused to a protein to form a fusion protein, wherein the protein is an antibody or an antibody fragment. In certain embodiments the interleukin is fused to an antibody to form a fusion protein. In certain embodiments, the interleukin is fused to an antibody fragment to form a fusion protein.
  • the interleukin is fused to a protein to form a fusion protein, wherein the protein is not an antibody or an antibody fragment.
  • Examples of interleukin fusion proteins with lumican that can be used in the present methods, uses, and combination therapies are disclosed in PCT publication WO 2020/068261 the contents of each of which are incorporated by reference.
  • the interleukin is fused to a protein to form a fusion protein, wherein the protein is not an antibody or an antibody fragment.
  • the interleukin is fused to a collagen-binding protein.
  • the collagen-binding protein is lumican.
  • the interleukin in the fusion protein is IL-12.
  • the interleukin in the fusion protein is IL-2.
  • the interleukin is fused to a protein to form a fusion protein, wherein the protein is not an antibody or an antibody fragment.
  • the interleukin is fused to an IL-2 receptor alpha chain, prostate-specific antigen cleavage sequence, matrix metalloproteinase cleavage sequence, or an alum-binding peptide.
  • the interleukin in the fusion protein is IL-12.
  • the interleukin in the fusion protein is IL-2.
  • the interleukin is IL-12 and is fused to a protein to form a fusion protein, wherein the protein is an antibody or an antibody fragment. In certain embodiments the interleukin is fused to an antibody to form a fusion protein. In certain embodiments, the interleukin is fused to an antibody fragment to form a fusion protein. In certain embodiments the interleukin is fused to a protein to form a fusion protein, wherein the protein is not an antibody or an antibody fragment. In certain embodiments, the interleukin is fused to an antibody that recognizes DNA/histone complexes. In certain embodiments, the interleukin is fused to the human monoclonal IgG1 antibody NHS76.
  • the interleukin can be fused to an IL-2 receptor alpha chain, prostate-specific antigen cleavage sequence, matrix metalloproteinase cleavage sequence, or antibody fragment scFv. Examples of such interleukin fusion proteins are disclosed in Puskas et al., 2011, Immunology, Jun;133(2):206-20. In certain embodiments, the interleukin can be fused to an alumn binding peptide (ABP).
  • ABSP alumn binding peptide
  • the interleukin is IL-2 and is fused to a protein to form a fusion protein, wherein the protein is an antibody or an antibody fragment. In certain embodiments the interleukin is fused to an antibody to form a fusion protein. In certain embodiments, the interleukin is fused to an antibody fragment to form a fusion protein. In certain embodiments the interleukin is fused to a protein to form a fusion protein, wherein the protein is not an antibody or an antibody fragment.
  • the interleukin is a fusion protein
  • the interleukin is a fusion protein, such as an Fc-fused interleukin, such as Fc-fused IL-2, IL-7, IL-10, IL-12, IL-15, or a combination thereof.
  • the interleukin is Fc-fused IL-2, IL-7, IL-10, IL-12, or a combination thereof.
  • the interleukin is Fc-fused IL-2, IL-12, IL-15, or a combination thereof.
  • the interleukin is Fc-fused IL-2.
  • the interleukin is Fc-fused IL-7. In another embodiment, the interleukin is Fc- fused IL-10. In another embodiment, the interleukin is Fc-fused IL-15. In a particular embodiment, the interleukin is Fc-fused IL-12. In other embodiments, the interleukin is not a fusion protein.
  • the immune checkpoint inhibitor when used in the methods and combination therapies disclosed herein, can be a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor, including an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti- CTLA-4 antibody
  • CTLA-4 inhibitors include, but are not limited to, ipilimumab (Yervoy®) and tremelimumab (ticilimumab), CBT-509, CS1002, BMS-986249, AGEN1181, AGEN1194, AGN2041, BA3071, ATOR-1015, ATOR-1144, ADV-1604 and BCD-145.
  • the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from ipilimumab (Yervoy®) and tremelimumab.
  • the CTLA-4 inhibitor can generally be administered systemically or intratumorally, and in particular embodiments the CTLA-4 inhibitor is an anti-CTLA-4 antibody that is administered intratumorally.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody
  • the CTLA-4 inhibitor inhibits the interaction between CTLA-4 on T cells and CD80 (B7.1) or CD86 (B7.2) on an antigen presenting cell such as a dendritic cell or a macrophage in the tumor microenvironment.
  • Examples of PD-1 inhibitors that can be used in accordance with the present disclosure include, but are not limited to, pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), AMP-224, AMP-514, or PDR001.
  • the PD-1 inhibitor can generally be administered systemically or intratumorally.
  • Examples of PD-L1 inhibitors that can be used in accordance with the present disclosure include, but are not limited to, atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), BMS-936559, or CK-301.
  • both the STING agonist and the cytokine are administered intratumorally into the primary tumor of the patient. It has been found that when particular STING agonists (e.g., Compound A) are administered intratumorally into the primary tumor, tumor growth is suppressed not only at the site of the primary tumor, but also at the site of distant tumors. Therefore, such STING agonists display an abscopal effect. Moreover, the STING agonist can augment T cell priming and inflammation in the tumor microenvironment, at both the site of injection and at distal legions. Cytokines, such as the interleukins, can expand T cells.
  • the present disclosure contemplates that the combination of a STING agonist and a cytokine results in increased, even synergistic, proliferation and/or function of T cells, which produces in an even larger abscopal effect than administering the STING agonist in the absence of a cytokine.
  • the present disclosure provides such combination therapies involving a STING agonist and a cytokine while reducing or limiting systemic toxicity from the cytokine.
  • the disclosure provides methods of treating both primary and distant tumors (including accessible and inaccessible cancers) by administering the combination therapies disclosed herein.
  • the methods described herein treat a tumor distant from the site of intratumoral administration of the STING agonist and/or the cytokine.
  • the present disclosure also provides a method of treating a patient, who is concurrently being treated systemically (e.g., intravenously, intramuscularly, subcutaneously, orally) or intratumorally with a STING agonist as described herein, comprising administering to the patient a cytokine as described herein.
  • the cytokine is administered intratumorally.
  • the cytokine is administered systemically (e.g., intravenously, intramuscularly, or subcutaneously).
  • the method further comprises administering a PD-1 inhibitor (e.g., an anti-PD- 1 antibody), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody), or a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody) as described herein to the patient.
  • a PD-1 inhibitor e.g., an anti-PD- 1 antibody
  • a PD-L1 inhibitor e.g., an anti-PD-L1 antibody
  • a CTLA-4 inhibitor e.g., an anti-CTLA-4 antibody
  • the combination therapies of the disclosure can be used to treat cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid gland, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney, or liver.
  • cancers treatable by the combination therapies of thee disclosure include rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, and renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; neoplasms of the CNS; spinal axis tumors; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial a
  • the combination therapies of the disclosure can be used to treat a cancer that is refractory or unresponsive to immune checkpoint inhibitory therapy.
  • cancers exhibit tumors of low immunogenicity.
  • Such cancers may include but are not limited to prostate cancer, pancreatic cancer, lymphoma, head and neck cancer, kidney cancer, melanoma, colon cancer, breast cancer, and lung cancer.
  • the cancer is selected from prostate cancer, pancreatic cancer, lymphoma, head and neck cancer, and kidney cancer.
  • the cancer is selected from melanoma, colon cancer, breast cancer, and lung cancer.
  • the combination therapies and methods of the disclosure are useful in treating solid tumors, such as tumors associated with melanoma or cancers of the kidney, lung, liver, colon, pancreas, brain, head and neck, bladder, prostate, breast, ovarian, cervix, and thyroid.
  • the present combination therapies and methods are useful in treating such tumors when they are the primary tumor.
  • the combination therapies and methods of the disclosure are useful in treating metastatic cancers that are capable of or have already spread to multiple organs.
  • the combination therapies of the disclosure can be used to reduce the recurrence of the tumors following the initial treatment.
  • compositions and Kits [00151] The disclosure further provides for a pharmaceutical composition comprising a STING agonist, a cytokine, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is an injectable pharmaceutical composition, e.g., for intratumoral injection.
  • the pharmaceutical acceptable carrier may include physiological saline or phosphate buffered saline (PBS).
  • PBS physiological saline or phosphate buffered saline
  • the present disclosure provides a kit for treating a disease or disorder, including cancer, the kit comprising a STING agonist and a cytokine.
  • the kit provides the cytokine formulated for intratumoral administration and the STING agonist formulated for intratumoral or systemic (e.g., intravenous, intramuscular, subcutaneous, or oral) administration.
  • the kit provides the STING agonist formulated for intratumoral administration and the cytokine formulated for intratumoral or systemic (e.g., intravenous, intramuscular, or subcutaneous) administration.
  • both the STING agonist and cytokine are formulated for intratumoral administration.
  • the kit further comprises a PD-1 inhibitor (e.g., an anti-PD- 1 antibody), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody), or a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody).
  • a PD-1 inhibitor e.g., an anti-PD- 1 antibody
  • a PD-L1 inhibitor e.g., an anti-PD-L1 antibody
  • a CTLA-4 inhibitor e.g., an anti-CTLA-4 antibody
  • the PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor are formulated for intratumoral or systemic (e.g., intravenous, intramuscular, or subcutaneous) administration.
  • both the cytokine and STING agonist are formulated for intratumoral administration, and the PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor is formulated for systemic (e.g., intravenous, intramuscular, or subcutaneous) administration.
  • the cytokine is formulated for intratumoral administration, and both the STING agonist and the PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor are formulated for systemic (e.g., intravenous, intramuscular, subcutaneous, or oral) administration.
  • both the cytokine and the PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor are formulated for intratumoral administration, and the STING agonist is formulated for systemic (e.g., intravenous, intramuscular, subcutaneous, or oral) administration.
  • both the STING agonist and the PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor are formulated for intratumoral administration, and cytokine is formulated for systemic (e.g., intravenous, intramuscular, or subcutaneous) administration.
  • the STING agonist, the cytokine, and the PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4 inhibitor are all formulated for intratumoral administration. 6.6.
  • the dosage of the STING agonist will vary depending on the particular STING agonist and the route of administration. In general, for systemic or intratumoral administration, the STING agonist can be administered at a dose in the range of 1-1000 ⁇ g/kg. For oral administration, the STING agonist can be administered at a dose in the range of 5-5000 ⁇ g/kg. [00155] In particular embodiments, where the STING agonist is a 2’3’-cGAMP analog, such as Compound A, the STING agonist can be administered intratumorally or systemically in the range of 1-100 ⁇ g/kg.
  • a 2’3’-cGAMP analog such as Compound A
  • a 2’3’-cGAMP analog such as Compound A
  • a dose e.g., a single or divided doses, in the range of 10- 6,500 ⁇ g, such as 50-6,500 ⁇ g.
  • a 2’3’-cGAMP analog, such as Compound A can be administered to a cancer patient at a dosage, e.g., a single or divided doses, in the range of 100-3,000 ⁇ g.
  • a 2’3’-cGAMP analog such as Compound A
  • a 2’3’-cGAMP analog can be administered to a cancer patient at a dosage e.g., a single or divided doses, in the range of 100-1,200 ⁇ g.
  • a 2’3’-cGAMP analog, such as Compound A can be administered to a cancer patient in the range of 10-50 ⁇ g, 10-100 ⁇ g, 10-200 ⁇ g, 50-200 ⁇ g, 100-200 ⁇ g, 100-400 ⁇ g, 100-500 ⁇ g, 100-800 ⁇ g, 200-400 ⁇ g, 400-600 ⁇ g, 400- 800 ⁇ g, 100-1,000 ⁇ g, 250-1,000 ⁇ g, 500-1,000 ⁇ g, 500-3,000 ⁇ g, 1,000-3,000 ⁇ g, 500- 4,500 ⁇ g, 1,000-4,500 ⁇ g, 500-6,500 ⁇ g, 1,000-6,500 ⁇ g, 2,000-6,500 ⁇ g, 3,000-6,500
  • the priming dose of can be administered to a cancer patient at a dosage in the range of 10-1,000 ⁇ g.
  • the priming dose of a 2’3’-cGAMP analog can be administered to a cancer patient in the range of 10-20 ⁇ g, 10-40 ⁇ g, 10-50 ⁇ g, 10-80 ⁇ g, 20-40 ⁇ g, 40-60 ⁇ g, 40-80 ⁇ g, 50-100 ⁇ g, 100-200 ⁇ g, 100-300 ⁇ g, 100-500 ⁇ g, 200-500 ⁇ g, 200-800 ⁇ g, 200-1,000 ⁇ g, 500-800 ⁇ g, or 500-1,000 ⁇ g.
  • a 2’3’-cGAMP analog such as Compound A
  • the priming dose of a 2’3’-cGAMP analog can be administered to a cancer patient at a dosage in the range of 0.15-20 ⁇ g/kg, such as 0.15-1 ⁇ g/kg, 0.25-1 ⁇ g/kg, 0.5-1 ⁇ g/kg, 0.5-2 ⁇ g/kg, 1-3 ⁇ g/kg, 1-5 ⁇ g/kg, 2- 5 ⁇ g/kg, 2-7 ⁇ g/kg, 1-10 ⁇ g/kg, 2-10 ⁇ g/kg, 3-10 ⁇ g/kg, 5-10 ⁇ g/kg, 5-15 ⁇ g/kg, 10-20 ⁇ g/kg, or 15-20 ⁇ g/kg.
  • 0.15-20 ⁇ g/kg such as 0.15-1 ⁇ g/kg, 0.25-1 ⁇ g/kg, 0.5-1 ⁇ g/kg, 0.5-2 ⁇ g/kg, 1-3 ⁇ g/kg, 1-5 ⁇ g/kg, 2- 5 ⁇ g/kg, 2-7 ⁇ g/kg, 1-10 ⁇ g/kg, 2
  • the maintenance doses can be administered to a cancer patient at a dosage in the range of 100-3,000 ⁇ g.
  • the maintenance doses of a 2’3’-cGAMP analog, such as Compound A can be administered to a cancer patient at a dosage in the range of 100-1,200 ⁇ g.
  • the maintenance doses of a 2’3’-cGAMP analog can be administered to a cancer patient in the range of 50-200 ⁇ g, 100-200 ⁇ g, 100-400 ⁇ g, 100-500 ⁇ g, 100-800 ⁇ g, 100-1,000 ⁇ g, 200-400 ⁇ g, 200-800 ⁇ g, 200-1,200 ⁇ g, 250-1,000 ⁇ g, 400-600 ⁇ g, 400-800 ⁇ g, 400-1,200 ⁇ g, 500-1,000 ⁇ g, 500-1,200 ⁇ g, 500-1,500 ⁇ g, 500-2,000 ⁇ g, 500-4,500 ⁇ g, 800-1,200 ⁇ g, 800-1,500 ⁇ g, 800-2,000 ⁇ g 1,000-2,000 ⁇ g, 1,000-3,000 ⁇ g, 1,000-4,500 ⁇ g, 2,000-4,500 ⁇ g, 500-6,500 ⁇ g, 1,000-6,500 ⁇ g, 1,500-6,500 ⁇ g, 2,000-6,500 ⁇ g, or
  • the maintenance doses of a 2’3’-cGAMP analog, such as Compound A can be administered to a cancer patient at a dosage in the range of 1-100 ⁇ g/kg, such as 1-50 ⁇ g/kg.
  • the maintenance doses of a 2’3’-cGAMP analog, such as Compound A can be administered to a cancer patient in the range of 1-10 ⁇ g/kg, 5-10 ⁇ g/kg, 5-20 ⁇ g/kg, 5- 30 ⁇ g/kg, 5-40 ⁇ g/kg, 5-50 ⁇ g/kg, 10-20 ⁇ g/kg, 10-30 ⁇ g/kg, 10-40 ⁇ g/kg, 10-50 ⁇ g/kg, 15- 20 ⁇ g/kg, 15-40 ⁇ g/kg, 20-30 ⁇ g/kg, 20-40 ⁇ g/kg, 20-50 ⁇ g/kg, 30-40 ⁇ g/kg, 30-50 ⁇ g/kg, 5-75 ⁇ g/kg, 10-75 ⁇ g/kg, 15-
  • the dosing cycle comprises administering a priming dose of a 2’3’-cGAMP analog, such as Compound A, on day 1 of a treatment cycle followed by administering a 2’3’-cGAMP analog, such as Compound A, under two maintenance dosing regimens.
  • the first maintenance dosing regimen comprises administering maintenance doses of a 2’3’-cGAMP analog, such as Compound A, on days 8, 15 and 22 (i.e., the first day of weeks 2, 3 and 4) of the treatment cycle, followed by a period of one week (i.e., week 5) where the 2’3’-cGAMP analog is not administered to the patient.
  • the second maintenance dosing regimen comprises administering a 2’3’-cGAMP analog, such as Compound A, on a biweekly dosing regimen.
  • a 2’3’-cGAMP analog such as Compound A
  • additional biweekly dosing of a 2’3’-cGAMP analog, such as Compound A can be administered to the patient.
  • a 2’3’-cGAMP analog, such as Compound A can be administered at week 10 of the dosing cycle, weeks 10 and 12 of the dosing cycle, weeks 10, 12, and 14 of the dosing cycle, weeks 10, 12, 14, and 16 of the dosing cycle, and so on.
  • the amount of the cytokine, such as an interleukin, administered to a cancer patient can be in the range of 0.001 ⁇ g/kg to 2 mg/kg, particularly 0.01 ⁇ g/kg to 1 mg/kg, depending on the cytokine or interleukin used.
  • the amount of the cytokine intratumorally administered to a cancer patient can be in the range of 0.01-100 ⁇ g/kg, such as in the range of 0.01-0.1 ⁇ g/kg, 0.01-1 ⁇ g/kg, 0.05-0.5 ⁇ g/kg, 0.05-1 ⁇ g/kg, 0.1-0.5 ⁇ g/kg, 0.1-1 ⁇ g/kg, 0.5-5 ⁇ g/kg, 1-10 ⁇ g/kg, 5-50 ⁇ g/kg, or 10-100 ⁇ g/kg.
  • the amount of IL-12 intratumorally administered to a cancer patient can range from 0.01, 0.05, 0.1, 0.5, or 1 ⁇ g/kg to 1.5, 5, 10, 25, 50, or 100 ⁇ g/kg. In some embodiments, the amount of IL-12 intratumorally administered to a cancer patient, can range from 0.01, 0.05, or 0.1 ⁇ g/kg to 0.5, 1, 1.5, or 2 ⁇ g/kg.
  • the amount of the cytokine intratumorally administered to a cancer patient can be in the range of 0.1 ⁇ g/kg to 1 mg/kg, such as in the range of 0.1-1 ⁇ g/kg, 0.1-10 ⁇ g/kg, 0.5-5 ⁇ g/kg, 0.5-50 ⁇ g/kg, 1-10 ⁇ g/kg, 1- 50 ⁇ g/kg, 1-100 ⁇ g/kg, 5-50 ⁇ g/kg, 5-100 ⁇ g/kg, 10-100 ⁇ g/kg, 50-500 ⁇ g/kg, or 100 ⁇ g/kg to 1 mg/kg.
  • the amount of IL-12 intratumorally administered to a cancer patient can range from 0.1, 0.5, 1, 1.5 ⁇ g/kg to 5, 10, 25, 50, 100, 500, or 1,000 ⁇ g/kg.
  • the immune checkpoint inhibitor can be administered to a cancer patient in amounts that have been approved by a relevant regulatory authority, such as the U.S. Food and Drug Administration.
  • the immune checkpoint inhibitor is a PD-1 inhibitor, such as pembrolizumab (Keytruda®) or nivolumab (Opdivo®) and is administered intravenously at a dose of 100-400 mg, such as 200 mg for pembrolizumab or 240 mg for nivolumab.
  • PD-1 inhibitor such as pembrolizumab (Keytruda®) or nivolumab (Opdivo®
  • 100-400 mg such as 200 mg for pembrolizumab or 240 mg for nivolumab.
  • the immune checkpoint inhibitor is a PD-L1 inhibitor, such as atezolizumab (Tecentriq®), avelumab (Bavencio®), or durvalumab (Imfinzi®), and is administered intravenously at a dose of 400-2,000 mg, such as 840- 1680 mg for atezolizumab, 800 mg for avelumab, or 1500 mg or 10 mg/kg for durvalumab.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor, such as ipilimumab (Yervoy®), and is administered intravenously at a dose of 2-5 mg/kg, such as 3 mg/kg. 6.7.
  • the STING agonist is administered under a dosing schedule that includes a priming dose followed by multiple maintenance doses.
  • a priming dose refers to a dose that is administered at lower doses than the maintenance doses to increase the tolerance of the body for a particular active agent (e.g., a STING agonist). It has been found that administration of a priming dose of the STING agonist improves the safety profile of the STING agonist and allows the compound to be delivered at higher maintenance dosage levels than would otherwise be tolerated. In general, the priming dosage amount will be less than the maintenance doses over the course of a given dosing cycle.
  • the disclosure provides novel dosing schedules for STING agonists based on specific dosing schedules requiring administration of a priming dose followed by administration of maintenance doses.
  • the novel STING agonist dosing schedules described herein also involve conjoint administration with a cytokine, and optionally, one or more immune checkpoint inhibitors, particularly PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor, as disclosed herein.
  • a cytokine and optionally, one or more immune checkpoint inhibitors, particularly PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor, as disclosed herein.
  • Using the combination of the STING agonist priming/maintenance dosing regimen conjointly with a cytokine is expected to provide an improved therapeutic index.
  • Particular STING agonists that can be administered using the disclosed priming/maintenance dosing schedules are described above.
  • the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is Compound A. In some embodiments, the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is not Compound A. In some embodiments, the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is Compound B. In some embodiments, the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is Compound C. In some embodiments, the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is Compound D. In some embodiments, the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is Compound E.
  • the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is Compound F. In some embodiments, the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is Compound G. In certain embodiments, the STING agonist to be administered with the disclosed priming/maintenance dosing schedule is administered as part of an ADC, such as those described herein. [00167] In some embodiments, the priming dose of the STING agonist can be administered in a quantity (by weight) that is 2- to 100-fold less than the individual maintenance doses in a given dosing cycle.
  • the priming dose can be administered in a quantity that is 2- to 70-fold less than, 2- to 50-fold less than, 2- to 30-fold less than, 2- to 20-fold less than, 2- to 10-fold less than, 10-to 50-fold less than, 10- to 30-fold less than, 10- to 20-fold less, or 20- to 30-fold less than the maintenance doses in a given cycle.
  • the priming dose can be administered in a quantity that is 2- to 4-fold less than the maintenance doses in a given cycle.
  • the priming dose can be administered in a quantity that is 2- to 5-fold less than the maintenance doses in a given cycle.
  • the priming dose can be administered in a quantity that is 2- to 8-fold less than the maintenance doses in a given cycle. In some embodiments, the priming dose can be administered in a quantity that is 3- to 5-fold less than the maintenance doses in a given cycle. In some embodiments, the priming dose can be administered in a quantity that is 3- to 8-fold less than the maintenance doses in a given cycle. In some embodiments, the priming dose can be administered in a quantity that is 4- to 8-fold less than the maintenance doses in a given cycle. [00168] In some embodiments, the priming dose can be delivered at a dose that is about 2- fold less than the maintenance doses over the course of a dosing cycle.
  • the priming dose can be delivered at a dose that is about 3-fold less than the maintenance doses over the course of a dosing cycle. In some embodiments, the priming dose can be delivered at a dose that is about 4-fold less than the maintenance doses over the course of a dosing cycle. In some embodiments, the priming dose can be delivered at a dose that is about 5-fold less than the maintenance doses over the course of a dosing cycle. In some embodiments, the priming dose can be delivered at a dose that is about 10-fold less than the maintenance doses over the course of a dosing cycle. In some embodiments, the priming dose can be delivered at a dose that is about 15-fold less than the maintenance doses over the course of a dosing cycle.
  • the priming dose can be delivered at a dose that is about 20-fold less than the maintenance doses over the course of a dosing cycle. In some embodiments, the priming dose can be delivered at a dose that is about 50- fold less than the maintenance doses over the course of a dosing cycle. In some embodiments, the priming dose can be delivered at a dose that is about 100-fold less than the maintenance doses over the course of a dosing cycle. [00169] It should be understood that the above relative amounts of priming dose to the individual maintenance doses can be expressed as a ratio.
  • the present disclosure provides a method of treating cancer comprising administering the combination of a STING agonist and a cytokine to a patient in need thereof, wherein the STING agonist is administered according to a dosing regimen that includes a 1:2 to 1:100 ratio of priming dose to individual maintenance doses, such as a ratio of 1:2, 2:5, 3:8, 1:3, 2:7, 1:4, 1:5, 1:6, 1:8, 1:9, 1:10, 1:11, 1:12, 1:15, 1:20, 1:30, 1:50, 1:75, or 1:100, including ranges created by these ratios, such as 1:2 to 1:3, 1:2 to 1:4, 1:2 to 1:5, 1:2 to 1:8, 1:2 to 1:10, 1:4 to 1:8, 1:4 to 1:10, 1:4 to 1:1
  • the present disclosure provides a method of treating cancer comprising administering the combination of a STING agonist and a cytokine to a patient in need thereof, wherein the STING agonist is administered according to a dosing regimen that includes a 1:4 or 1:5 ratio of priming dose to individual maintenance doses, or a ratio in the range of 1:3 to 1:6, such as 1:3 to 1:5, 1:4 to 1:6, or 1:4 to 1:5.
  • the ratio is 1:8 or 1:10, or a ratio in the range of 1:5 to 1:15, such as 1:6 to 1:12, 1:8 to 1:12, 1:8 to 1:10, or 1:9 to 1:10.
  • the priming dose can be administered on day 1 of a treatment cycle and the maintenance doses can be administered thereafter at a dosing schedule as described above.
  • the first maintenance dose can be administered at least 2 days following the administration of the priming dose, i.e., on day 3.
  • the first maintenance dose can be administered 2, 3, 4, 5, 6, 7, 8, 9, or 10 days following administration of the priming dose.
  • the dosing cycle comprises administering a priming dose of the STING agonist on day 1 of a treatment cycle followed by administering maintenance doses of the STING agonist on days 8, 15 and 22 (i.e., the first day of weeks 2, 3 and 4) of the treatment cycle, followed by a period of one week (i.e., week 5) where the STING agonist is not administered to the patient.
  • the maintenance dosing cycle can be repeated, or a modified maintenance dosing schedule can be employed.
  • the dosing cycle comprises administering a priming dose of the priming dose on day 1 of a treatment cycle followed by administering maintenance doses of the STING agonist on days 8 and 22 of the dosing schedule (i.e., biweekly dosing).
  • the maintenance dosing cycle can be repeated or a modified maintenance dosing schedule can be employed. 7. EXAMPLES Example 1.
  • Anti-PD-L1 antibody (BE0101) was purchased from BioXcell (Lebanon, NH), IL-2 (212- 12), IL-12 (210-12), and IL-15 (210-15) were purchased from PeproTech (Rocky Hill, NJ). [00176] An increase in anti-tumor effect on the primary tumor was observed with a triple combination of Compound A, anti-PD-L1 antibody, and cytokines IL-2, IL-12, or IL-15 when compared to treatment with the double combination of Compound A and anti-PD-L1 antibody (panel A of FIG.1).
  • mice were mock treated with PBS or treated intraperitoneally with 200 ⁇ g of an anti-PD-L1 antibody and intratumorally on their right site (primary) with 1 ⁇ g of Compound A alone or in combination with IL-7 (5 ⁇ g) or IL-10 (5 ⁇ g).
  • Cytokines and Compound A were administered in a vehicle of 50 ⁇ L of PBS containing 0.2 mg/mL bovine serum albumin. Tumor volumes were measured every 2-3 days and survival was monitored daily.
  • Anti-PD- L1 antibody (BE0101) was purchased from BioXcell (Lebanon, NH), IL-7 (217-17) and IL- 10 (210-10) were from PeproTech (Rocky Hill, NJ). [00180] A significant increase in anti-tumor effect on the primary tumor was observed with a triple combination of Compound A, anti-PD-L1 antibody, and cytokines IL-7 or IL-10 when compared to treatment with the double combination of Compound A and anti-PD-L1 antibody (panel A of FIG.2).
  • mice Female C57BL6 mice (Jackson Laboratory) at the age of 7-8 weeks were implanted subcutaneously with 10 6 B16F10 (ATCC CRL-6475) melanoma cells into the right flank (primary tumor) on day 0 and left flank (distal tumor) on day 2. Tumors were measured on day 6 and mice were regrouped so that each group had similar average tumor volumes. Each group contained 5 mice.
  • mice were mock treated with PBS or treated intraperitoneally with 200 ⁇ g of an anti-PD-L1 antibody and intratumorally on their right site (primary) with 1 ⁇ g of Compound A alone; with 50 ng, 200 ng, or 1 ⁇ g of IL-12 alone; or with a combination of 1 ⁇ g of Compound A and 50 ng, 200 ng, or 1 ⁇ g of IL-12.
  • Cytokines and Compound A were administered in a vehicle of 50 ⁇ L of PBS containing 0.2 mg/mL bovine serum albumin. Tumor volumes were measured every 2-3 days and survival was monitored daily. Body weight change (%) was measured over time from day 6 before first treatment.
  • Anti-PD-L1 antibody (BE0101) was purchased from BioXcell (Lebanon, NH), IL-12 (210-12) was purchased from PeproTech (Rocky Hill, NJ). [00184] An increase in anti-tumor effect on the primary tumor was observed with a triple combination of Compound A, anti-PD-L1 antibody, and IL-12 when compared to treatment with the double combination of Compound A and anti-PD-L1 antibody or IL-12 and anti-PD- L1 antibody (panel A of each of FIGs.3A, 3B, and 3C).
  • Anti-PD-L1 antibody (BE0101) was purchased from BioXcell (Lebanon, NH), IL-12 (210-12) was purchased from PeproTech (Rocky Hill, NJ). [00189] Compared to the double combination of Compound A and anti-PD-L1 antibody, increased anti-tumor effect on the primary tumor was observed when a triple combination of Compound A, anti-PD-L1 antibody, and 3 ng, 10 ng, or 30 ng of IL-12 was used (panel A of FIG.4).
  • a dose-responsive anti-tumor effect on the distal untreated tumor i.e., an abscopal effect
  • This dose-responsive anti-tumor effect was also reflected in the increased mouse survival for the various triple combinations (panel B of FIG.4).
  • the initial transient and minimal ( ⁇ 5%) body weight reduction followed by rapid recovery illustrated the low toxicity of the various combinations (panel C of FIG.4).
  • Example 5 The initial transient and minimal ( ⁇ 5%) body weight reduction followed by rapid recovery illustrated the low toxicity of the various combinations.
  • mice were mock treated or treated intratumorally on their right flank (primary) with 1 ⁇ g of Compound A and 50 ng of IL-12-Fc, or intraperitoneally with 200 ⁇ g of an anti-PD-L1 antibody and intratumorally on their right site (primary) with 1 ⁇ g of Compound A alone, 50 ng of IL-12-Fc alone, or a combination of 1 ⁇ g of Compound A and 50 ng of IL-12-Fc.
  • Cytokines and Compound A were administered in a vehicle of 50 ⁇ L of PBS containing 0.2 mg/mL bovine serum albumin. Tumor volumes were measured every 2-3 days and survival was monitored daily.
  • the IL-12-Fc protein comprised two subunits of mouse interleukine-12 (p35 and p40), each fused to the Fc domain of human IgG1, with the following amino acid sequences: (SEQ ID NO: 1) Mu IL-12 p35-Linker-huIgG1 Fc (Hole): (SEQ ID NO: 2) Mu IL-12 p40-Linker-huIgG1 Fc (Knob): NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK Signal peptides are underlined, and linker sequences are bold+italic.
  • cDNA encoding each subunit was cloned into pcDNA3.4-TOPO vector (Invitrogen, A14697).
  • both plasmids were transfected into CHO (ATCC (CCL-61) cells using ExpiFectamineTM CHO Transfection Kit (Gibco, A29129) following the manufacturer’s protocol. Seven days after transfection, the culture media were collected and the IL-12-Fc protein was loaded onto a 5ml HiTrap protein A column (GE, 17-0403-01) on a Bio-Rad NGC Chromatography system (Bio-Rad, NGC Quest 10, 7880001).
  • mice contained 5 mice. Subsequently and on the same day 9 and on days 12, 15, and 18, mice were mock treated with PBS or treated intraperitoneally with 200 ⁇ g of an anti-PD-L1 antibody and intratumorally on their right site (primary) with 1 ⁇ g of Compound A alone or in combination with 5 ng, 17 ng, or 50 ng of IL-12-Fc. Cytokines and Compound A were administered in a vehicle of 50 ⁇ L of PBS containing 0.2 mg/mL bovine serum albumin. Tumor volumes were measured every 2-3 days and survival was monitored daily.
  • Anti-PD- L1 antibody (BE0101) was purchased from BioXcell (Lebanon, NH). The IL-12-Fc protein was obtained as described above.
  • Anti-PD-L1 antibody (BE0101) was purchased from BioXcell (Lebanon, NH).
  • the fusion protein designated mIL-12-MSA-Lumican contains (from N-terminal to C-terminal) murine interleuline-12, murine serum albumin, and Lumican, a collagen-binding moiety which anchors the molecule in tumors.
  • the encoding cDNA was cloned into pcDNA3.4-TOPO vector (Invitrogen, A14697) and transfected into CHO cells using ExpiFectamineTM CHO Transfection Kit (Gibco, A29129) following the manufacturer’s protocol.
  • Double combination of Compound A and anti-PD-L1 antibody showed anti-tumor effect in primary tumors but limited anti-tumor effect in distal tumors.
  • triple combination of Compound A, anti-PD-L1 antibody, and IL-12-Fc or mIL-12-MSA-Lumican showed anti-tumor effect in primary and distal tumors (panel A of FIG.7).
  • Mice survival showed to be dose-dependent in groups treated with mIL-12-MSA-Lumican (panel B of FIG. 7).
  • mice Female C57BL6 mice (Jackson Laboratory) at the age of 7-8 weeks were implanted subcutaneously with 10 6 B16F10 (ATCC CRL-6475) melanoma cells into the right flank (primary tumor) on day 0 and left flank (distal tumor) on day 2. Tumors were measured on day 9 and mice were regrouped so that each group had similar average tumor volumes. Each group contained 5 mice.
  • mice were mock treated with PBS or: 1) treated intratumorally on their right flank (primary) with 60 ng of mIL-12-MSA-Lumican and treated intraperitoneally with 200 ⁇ g of an anti-PD-L1 antibody; 2) treated intratumorally on their right flank (primary) with 1 ⁇ g of Compound A and treated intraperitoneally with 200 ⁇ g of an anti-PD-L1 antibody; 3) treated intratumorally on their right flank (primary) with 1 ⁇ g of Compound A and treated intratumorally on their right flank (primary) with 60 ng of mIL-12-MSA-Lumican or 4) treated intratumorally on their right flank (primary) with 1 ⁇ g of Compound A and with 60 ng of mIL-12-MSA-Lumican and treated intraperitoneally with 200 ⁇ g of an anti-PD-L1 antibody.
  • Cytokines and Compound A were administered in a vehicle of 50 ⁇ L of PBS containing 0.5% mouse serum. Tumor volumes were measured every 2-3 days and survival was monitored daily.
  • Anti-PD-L1 antibody (BE0101) was purchased from BioXcell (Lebanon, NH). [00209] Double combination of mIL-12-MSA-Lumican and anti-PD-L1 antibody showed partial anti-tumor effect in primary tumors but no anti-tumor effect in distal tumors. Double combination of Compound A and anti-PD-L1 antibody showed anti-tumor effect in primary tumors but limited anti-tumor effect in distal tumors.
  • Double combination of Compound A and mIL-12-MSA-Lumican showed anti-tumor effect in primary tumors but reduced anti- tumor effect in distal tumors.
  • Triple combination of Compound A, anti-PD-L1 antibody, and mIL-12-MSA-Lumican showed anti-tumor effect in primary and distal tumors (panel A of FIG.8).
  • mice survival was greatest in mice treated with the triple combination versus any of the three double combinations (panel B of FIG.8).
  • Example 9 Tumor Growth in Naive Mice and Pre-treated Mice.

Abstract

La divulgation concerne, entre autres, des méthodes et des utilisations pour le traitement d'une maladie ou d'un trouble, en particulier de tumeurs d'un patient atteint d'un cancer, comprenant l'administration conjointe de doses efficaces d'un agoniste de STING, d'une cytokine et d'un inhibiteur de point de contrôle immunitaire facultatif au patient, l'agoniste de STING ou la cytokine étant administré par voie intratumorale au patient.
PCT/US2022/074120 2021-07-23 2022-07-25 Polythérapies à base d'agonistes de sting comprenant des cytokines WO2023004440A2 (fr)

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